This invention relates a treatment of psychiatric disorders and neurological diseases including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress, by administration of certain [1,5-a]-pyrazolo-1,3,5-triazines, [1,5-a]-1,2,3-triazolo-1,3,5-triazines, [1,5-a]-pyrazolo-pyrimidines and [1,5-a]-1,2,3-triazolo-pyrimidines.
Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin(POMC)xe2x80x94derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].
Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer""s disease, Parkinson""s disease, Huntington""s disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E. B. De Souza, Hosp. Practice 23:59 (1988)].
In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].
There has also been a role postulated for CRF in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist a-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces xe2x80x9canxiolytic-likexe2x80x9d effects that are qualitatively similar to the benzodiazepines [C. W. Berridge and A. J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the xe2x80x9canxiogenicxe2x80x9d effects of CRF in both the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro15-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)].
The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (xcex1-helical CRF9-41) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces xe2x80x9canxiolytic-likexe2x80x9d effects qualitatively similar to the benzodiazepines [for review see G. F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p221 (1990)].
Several publications describe corticotropin releasing factor antagonist compounds and their use to treat psychiatric disorders and neurological diseases. Examples of such publications include DuPont Merck PCT application US94/11050, Pfizer WO 95/33750, Pfizer WO 95/34563, Pfizer WO 95/33727 and Pfizer EP 0778 277 A1.
Insofar as is known, [1,5-a]-pyrazolo-1,3,5-triazines, [1,5-a]-1,2,3-triazolo-1,3,5-triazines, [1,5-a]-pyrazolo-pyrimidines and [1,5-a]-1,2,3-triazolo-pyrimidines, have not been previously reported as corticotropin releasing factor antagonist compounds useful in the treatment of psychiatric disorders and neurological diseases. However, there have been publications which teach some of these compounds for other uses.
For instance, EP 0 269 859 (Qstuka, 1988) discloses pyrazolotriazine compounds of the formula 
where R1 is OH or alkanoyl, R2 is H, OH, or SH, and R3 is an unsaturated heterocyclic group, naphthyl or substituted phenyl, and states that the compounds have xanthine oxidase inhibitory activity and are useful for treatment of gout.
EP 0 594 149 (Ostuka, 1994) discloses pyrazolotriazine and pyrazolopyrimidine compounds of the formula 
where A is CH or N, R0 and R3 are H or alkyl, and R1 and R2 are H, alkyl, alkoxyl, alkylthio, nitro, etc., and states that the compounds inhibit androgen and are useful in treatment of benign prostatic hypertrophy and prostatic carcinoma.
U.S. Pat. No. 3,910,907 (ICI, 1975) discloses pyrazolotriazines of the formula: 
where R1 is CH3, C2H5 or C6H5, X is H, C6H5, m-CH3C6H4, CN, COOEt, Cl, I or Br, Y is H, C6H5, o-CH3C6H4, or p-CH3C6H4, and Z is OH, H, CH3, C2H5, C6H5, n-C3H7, i-C3H7, SH, SCH3, NHC4H9, or N(C2H5)2, and states that the compounds are c-AMP phosphodiesterase inhibitors useful as bronchodilators.
U.S. Pat. No. 3,995,039 discloses pyrazolotriazines of the formula: 
where R1 is H or alkyl, R2 is H or alkyl, R3 is H, alkyl, alkanoyl, carbamoyl, or lower alkylcarbamoyl, and R is pyridyl, pyrimidinyl, or pyrazinyl, and states that the compounds are useful as bronchodilators.
U.S. Pat. No. 5,137,887 discloses pyrazolotriazines of the formula 
where R is lower alkoxy, and teaches that the compounds are xanthine oxidase inhibitors and are useful for treatment of gout.
U.S. Pat. No. 4,892,576 discloses pyrazolotriazines of the formula 
where X is O or S, Ar is a phenyl, naphthyl, pyridyl or thienyl group, R6-R8 are H, alkyl, etc., and R9 is H, alkyl, phenyl, etc. The patent states that the compounds are useful as herbicides and plant growth regulants.
U.S. Pat. No. 5,484,760 and WO 92/10098 discloses herbicidal compositions containing, among other things, a herbicidal compound of the formula 
where A can be N, B can be CR3, R3 can be phenyl or substituted phenyl, etc., R is xe2x80x94N(R4)SO2R5 or xe2x80x94SO2N(R6)R7 and R1 and R2 can be taken together to form 
where X, Y and Z are H, alkyl, acyl, etc. and D is O or S.
U.S. Pat. No. 3,910,907 and Senga et al., J. Med. Chem., 1982, 25, 243-249, disclose triazolotriazines cAMP phosphodiesterase inhibitors of the formula 
where Z is H, OH, CH3, C2H5, C6H5, n-C3H7, iso-C3H7, SH, SCH3, NH(n-C4H9), or N(C2H5)2, R is H or CH3, and R1 is CH3 or C2H5. The reference lists eight therapeutic areas where inhibitors of cAMP phosphodiesterase could have utility: asthma, diabetes mellitus, female fertility control, male infertility, psoriasis, thrombosis, anxiety, and hypertension.
WO95/35298 (Otsuka, 1995) discloses pyrazolopyrimidines and states that they are useful as analgesics. The compounds are represented by the formula 
where Q is carbonyl or sulfonyl, n is 0 or 1, A is a single bond, alkylene or alkenylene, R1 is H, alkyl, etc., R2 is naphthyl, cycloalkyl, heteroaryl, substituted phenyl or phenoxy, R3 is H, alkyl or phenyl, R4 is H, alkyl, alkoxycarbonyl, phenylalkyl, optionally phenylthio-substituted phenyl, or halogen, R5 and R6 are H or alkyl.
EP 0 591 528 (Otsuka,1991) discloses anti-inflammatory use of pyrazolopyrimidines represented by the formula 
where R1, R2, R3 and R4 are H, carboxyl, alkoxycarbonyl, optionally substituted alkyl, cycloalkyl, or phenyl, R5 is SR6 or NR7R8, R6 is pyridyl or optionally substituted phenyl, and R7 and R8 are H or optionally substituted phenyl.
Springer et al, J. Med. Chem., 1976, vol. 19, no. 2, 291-296 and Springer U.S. Pat. Nos. 4,021,556 and 3,920,652 disclose pyrazolopyrimidines of the formula 
where R can be phenyl, substituted phenyl or pyridyl, and their use to treat gout, based on their ability to inhibit xanthine oxidase.
Joshi et al., J. Prakt. Chemie, 321, 2, 1979, 341-344, discloses compounds of the formula 
where R1 is CF3, C2F5, or C6H4F, and R2 is CH3, C2H5, CF3, or C6H4F.
Maquestiau et al., Bull. Soc. Belg., vol.101, no. 2, 1992, pages 131-136 discloses a pyrazolo[1,5-a]pyrimidine of the formula 
Ibrahim et al., Arch. Pharm. (weinheim) 320, 487-491 (1987) discloses pyrazolo[1,5-a]pyrimidines of the formula 
where R is NH2 or OH and Ar is 4-phenyl-3-cyano-2-aminopyrid-2-yl.
Other references which disclose azolopyrimidines inclued EP 0 511 528 (Otsuka, 1992), U.S. Pat. No. 4,997,940 (Dow, 1991), EP 0 374 448 (Nissan, 1990), U.S. Pat. No. 4,621,556 (ICN,1997), EP 0 531 901 (Fujisawa, 1993), U.S. Pat. No. 4,567,263 (BASF, 1986), EP 0 662 477 (Isagro, 1995), DE 4 243 279 (Bayer, 1994), U.S. Pat. No. 5,397,774 (Upjohn, 1995), EP 0 521 622 (Upjohn, 1993), WO 94/109017 (Upjohn, 1994), J. Med. Chem., 24, 610-613 (1981), and J. Het. Chem., 22, 601 (1985).
In accordance with one aspect, the present invention provides novel compounds, pharmaceutical compositions and methods which may be used in the treatment of affective disorder, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer""s disease, gastrointestinal disease, anorexia nervosa or other feeding disorder, drug or alcohol withdrawal symptoms, drug addiction, inflammatory disorder, fertility problems, disorders, the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, or a disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic, phobias, obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; pain perception such as fibromyalgia; mood disorders such as depression, including major depression, single episode depression, recurrent depression, child abuse induced depression, and postpartum depression; dysthemia; bipolar disorders; cyclothymia; fatigue syndrome; stress-induced headache; cancer, human immunodeficiency virus (HIV) infections; neurodegenerative diseases such as Alzheimer""s disease, Parkinson""s disease and Huntington""s disease; gastrointestinal diseases such as ulcers, irritable bowel syndrome, Crohn""s disease, spastic colon, diarrhea, and post operative ilius and colonic hypersensitivity associated by psychopathological disturbances or stress; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone (ADH); obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage (e.g., cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; cardiovascular and hear related disorders including hypertension, tachycardia and congestive heart failure; stroke; immune dysfunctions including stress induced immune dysfunctions (e.g., stress induced fevers, porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, sheering stress in sheep or human-animal interaction related stress in dogs); muscular spasms; urinary incontinence; senile dementia of the Alzheimer""s type; multiinfarct dementia; amyotrophic lateral sclerosis; chemical dependencies and addictions (e.g., dependencies on alcohol, cocaine, heroin, benzodiazepine, or other drugs); drug and alcohol withdrawal symptoms; osteoporosis; psychosocial dwarfism and hypoglycemia in a mammal.
The present invention provides novel compounds which bind to corticotropin releasing factor receptors, thereby altering the anxiogenic effects of CRF secretion. The compounds of the present invention are useful for the treatment of psychiatric disorders and neurological diseases, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and clonic hypersensitivity associated with psychopathological disturbance and stress in a mammal.
According to another aspect, the present invention provides novel compounds of Formulae (1) and (2) (described below) which are useful as antagonists of the corticotropin releasing factor. The compounds of the present invention exhibit activity as corticotropin releasing factor antagonists and appear to suppress CRF hypersecretion. The present invention also includes pharmaceutical compositions containing such compounds of Formulae (1) and (2), and methods of using such compounds for the suppression of CRF hypersecretion, and/or for the treatment of anxiogenic disorders.
According to yet another aspect of the invention, the compounds provided by this invention (and especially labelled compounds of this invention) are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF receptor.
[1] The present invention comprises a method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer""s disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals comprising administering to the mammal a therapeutically effective amount of a compound of Formulae (1) or (2): 
and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof, wherein:
A is N or CR;
Z is N or CR2;
Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar optionally substituted with 1 to 5 R4 groups and each Ar is attached to an unsaturated carbon atom;
R is independently selected at each occurrence from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, halo, CN, C1-C4 haloalkyl;
R1 is independently selected at each occurrence from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halo, CN, C1-C4 haloalkyl, C1-C12 hydroxyalkyl, C2-C12 alkoxyalkyl, C2-C10 cyanoalkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, NR9R10, C1-C4 alkyl-NR9R10, NR9COR10, OR11, SH or S(O)nR12;
R2 is selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, C1-C4 hydroxyalkyl, halo, CN,xe2x80x94NR6R7, NR9COR10, xe2x80x94NR6S(O)nR7, S(O)nNR6R7, C1-C4 haloalkyl, xe2x80x94OR7, SH or xe2x80x94S(O)nR12;
R3 is selected from:
H, OR7, SH, S(O)nR13, COR7, CO2R7, OC(O)R13, NR8COR7, N(COR7)2, NR8CONR6R7, NR8CO2R13, NR6R7, NR6aR7a, N(OR7)R6, CONR6R7, aryl, heteroaryl and heterocyclyl, or
C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C4-C12 cycloalkylalkyl or C6-C10 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl and heterocyclyl;
R4 is independently selected at each occurrence from: C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, NO2, halo, CN, C1-C4 haloalkyl, NR6R7, NR8COR7, NR8CO2R7, COR7, OR7, CONR6R7, CO(NOR9)R7, CO2R7, or S(O)nR7, where each such C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl and C4-C12 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, NO2, halo, CN, NR6R7, NR8COR7, NR8CO2R7, COR7 OR7, CONR6R7, CO2R7, CO(NOR9)R7, or S(O)nR7;
R6 and R7, R6a and R7a are independently selected at each occurrence from:
H,
C1-C10 alkyl, C3-C10 alkenyl, C3-C10alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl,
aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl);
xe2x80x83alternatively, NR6R7 and NR6aR7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups;
R8 is independently selected at each occurrence from H or C1-C4 alkyl;
R9 and R10 are independently selected at each occurrence from H, C1-C4 alkyl, or C3-C6 cycloalkyl;
R11is selected from H, C1-C4 alkyl, C1-C4 haloalkyl, or C3-C6 cycloalkyl;
R12 is C1-C4 alkyl or C1-C4 haloalkyl;
R13 is selected from C1-C4 alkyl, C1-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl(C1-C4 alkyl)-, heteroaryl or heteroaryl(C1-C4 alkyl)-;
R14 is selected from C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, or C4-C12 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR15, COR15, CO2R15, OC(O)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15, NR16R15, CONR16R15, and C1-C6 alkylthio, C1-C6 alkylsulfinyl and C1-C6 alkylsulfonyl;
R15 and R16 are independently selected at each occurrence from H, C1-C6 alkyl, C3-C10 cycloalkyl, C4-C16 cycloalkylalkyl, except that for S(O)nR15, R15 cannot be H;
aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR15, COR15, CO2R15, OC(O)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15, NR16R15, and CONR16R15;
heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or 2,3-dihydrobenzofuranyl, each being optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR15, xe2x80x94COR15, CO2R15, OC(O)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15, NR16R15, and CONR16R15;
heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR15, COR15, CO2R15, OC(O)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15, NR15R16, and CONR16R15;
n is independently at each occurrence 0, 1 or 2.
[2] Preferred methods of the present invention are methods in wherein in the compound of Formulae (1) or (2), Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 R4 substituents.
[3] Further preferred methods of the above invention are methods wherein, in the compound of Formulae (1) or (2), A is N, Z is CR2, Ar is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-trimethylphenyl, R1 and R2 are CH3, and R3 is NR6aR7a.
[4] The present invention comprises compounds of Formulae (1) or (2): 
and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein:
A is N or CR;
Z is N or CR2;
Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar optionally substituted with 1 to 5 R4 groups and each Ar is attached to an unsaturated carbon atom;
R is independently selected at each occurrence from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, halo, CN, C1-C4 haloalkyl;
R1 is independently selected at each occurrence from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halo, CN, C1-C4 haloalkyl, C1-C12 hydroxyalkyl, C2-C12 alkoxyalkyl, C2-C10 cyanoalkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, NR9R10, C1-C4 alkyl-NR9R10, NR9COR10, OR11, SH or S(O)nR12;
R2 is selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C10cycloalkylalkyl, C1-C4 hydroxyalkyl, halo, CN, xe2x80x94NR6R7, NR9COR10, xe2x80x94NR6S(O)nR7, S(O)nNR6R7, C1-C4 haloalkyl, xe2x80x94OR7, SH or xe2x80x94S(O)nR12;
R3 is selected from:
H, OR7, SH, S(O)nR13, COR7, CO2R7, OC(O)R13, NR8COR7, N(COR7)2, NR8CONR6R7, NR8CO2R13, NR6R7, NR6aR7a, N(OR7)R6, CONR6R7, aryl, heteroaryl and heterocyclyl, or
C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C4-C12 cycloalkylalkyl or C6-C10 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl and heterocyclyl;
R4 is independently selected at each occurrence from: C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, NO2, halo, CN, C1-C4 haloalkyl, NR6R7, NR8COR7, NR8CO2R7, COR7, OR7, CONR6R7, CO(NOR9)R7, CO2R7, or S(O)nR7, where each such C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl and C4-C12 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, NO2, halo, CN, NR6R7, NR8COR7, NR8CO2R7, COR7OR7, CONR6R7, CO2R7, CO(NOR9)R7, or S(O)nR7;
R6 and R7, R6a and R7a are independently selected at each occurrence from:
H,
C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR 13 COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl,
aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl),
xe2x80x83alternatively, NR6R7 and NR6aR7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups;
R8 is independently selected at each occurrence from H or C1-C4 alkyl;
R9 and R10 are independently selected at each occurrence from H, C1-C4 alkyl, or C3-C6 cycloalkyl;
R11 is selected from H, C1-C4 alkyl, C1-C4 haloalkyl, or C3-C6 cycloalkyl;
R12 is C1-C4 alkyl or C1-C4 haloalkyl;
R13 is selected from C1-C4 alkyl, C1-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl(C1-C4 alkyl)-, heteroaryl or heteroaryl(C1-C4 alkyl)-;
R14 is selected from C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, or C4-C12 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR15, COR15, CO2R15, OC(O)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15, NR16R15, CONR16R15, and C1-C6 alkylthio, C1-C6 alkylsulfinyl and C1-C6 alkylsulfonyl;
R15 and R16 are independently selected at each occurrence from H, C1-C6 alkyl, C3-C10 cycloalkyl, C4-C16 cycloalkylalkyl, except that for S(O)nR15, R15 cannot be H;
aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR15, COR15, CO2R15, OC(O)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15, NR16R15, and CONR16R15;
heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or 2,3-dihydrobenzofuranyl, each being optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR15 xe2x80x94COR15, CO2R15, OC(O)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15, NR16R15, and CONR16R15;
heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR15, COR15, CO2R15, OC(O)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15, NR15R16, and CONR16R15;
n is independently at each occurrence 0, 1 or 2,
with the provisos that:
(1) when A is N, Z is CR2, R2 is H, R3 is xe2x80x94OR7 or xe2x80x94OCOR13, and R7 is H, then R1 is not H, OH or SH;
(2) when A is N, Z is CR2, R1 is CH3 or C2H5, R2 is H, and R3 is OH, H, CH3, C2H5, C6H5, n-C3H7, i-C3H7, SH, SCH3, NHC4H9, or N(C2H5)2, then Ar is not phenyl or m-CH3-phenyl;
(3) when A is N, Z is CR2, R2 is H, and Ar is pyridyl, pyrimidinyl or pyrazinyl, and R3 is NR6aR7a, then R6a and R7a are not H or alkyl;
(4) when A is N, Z is CR2, and R2 is SO2NR6R7, then R3 is not OH or SH;
(5) when A is CR and Z is CR2, then R2 is not xe2x80x94NR6SO2R7 or xe2x80x94SO2NR6R7;
(6) when A is N, Z is CR2 and R2 is xe2x80x94NR6SO2R7 or xe2x80x94SO2NR6R7, then R3 is not OH or SH;
(7) when A is N, Z is CR2, R1 is methyl or ethyl, R2 is H, and R3 is H, OH, CH3, C2H5, C6H5, n-C3H7, iso-C3H7, SH, SCH3, NH(n-C4H9), or N(C2H5)2, then Ar is not unsubstituted phenyl or m-methylphenyl;
(8) when A is CR, Z is CR2, R2 is H, phenyl or alkyl, R3 is NR8COR7 and Ar is phenyl or phenyl substituted with phenylthio, then R7 is not aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocycly(C1-C4 alkyl);
(9) when A is CR, Z is CR2, R2 is H or alkyl, Ar is phenyl, and R3 is SR13 or NR6aR7a, then R13 is not aryl or heteroaryl and R6a and R7a are not H or aryl; or
(10) when A is CH, Z is CR2, R1 is OR11, R2 is H, R3 is OR7 and R7 and R11 are both H, then Ar is not phenyl, p-Br-phenyl, p-Cl-phenyl, p-NHCOCH3-phenyl, p-CH3-phenyl, pyridyl or naphthyl;
(11) when A is CH, Z is CR2, R2 is H, Ar is unsubstituted phenyl, and R3 is CH3, C2H5, CF3 or C6H4F, then R1 is not CF3 or C2F5;
(12) when A is CR, R is H, Z is CR2, R2 is OH, and R1 and R3 are H, then Ar is not phenyl;
(13) when A is CR, R is H, Z is CR2, R2 is OH or NH2, R1 and R3 are CH3, then Ar is not 4-phenyl-3-cyano-2-aminopyrid-2-yl.
[5] Preferred compounds of the above invention are compounds of Formulae (1) and (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof with the additional provisos that: (1) when A is N, R1 is H, C1-C4 alkyl, halo, CN, C1-C12 hydroxyalkyl, C1-C4 alkoxyalkyl or SO2(C1-C4 alkyl), R3 is NR6aR7a and R6a is unsubstituted C1-C4 alkyl, then R7a is not phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl, benzofuranyl, benzothiazolyl, indolyl or C3-C6 cycloalkyl; and (2) A is N, R1 is H, C1-C4 alkyl, halo, CN, C1-C12 hydroxyalkyl, C1-C4 alkoxyalkyl or SO2(C1-C4 alkyl), R3 is NR6aR7a and R7a is unsubstituted C1-C4 alkyl, then R6a is not phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl, benzofuranyl, benzothiazolyl, indolyl or C3-C6 cycloalkyl.
[6] Preferred compounds of the above invention also include compounds of Formulae (1) and (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 R4 substituents.
[7] Preferred compounds of the above invention also include compounds of Formulae (1) and (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein A is N, Z is CR2, Ar is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-trimethylphenyl, R1 and R2 are CH3, and R3 is NR6aR7a.
[11] More preferred compounds of the above invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein A is N.
[12] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.
[13] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R4 substituents.
[14] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R3 is NR6aR7a or OR7.
[15] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R4 substituents, and R3 is NR6aR7a or OR7.
[16] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Z is CR2.
[17] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R4 substituents.
[18] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R3 is NR6aR7a or OR7.
[19] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a is independently selected from:
H,
C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl,
aryl, aryl(C1-C4 alkyl)-, heteroaryl, heteroaryl(C1-C4 alkyl)-, heterocyclyl or heterocyclyl(C1-C4 alkyl)-; and
R7a is independently selected at each occurrence from:
H,
C5-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl,
aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl);
alternatively, NR6R7 and NR6aR7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups.
[20] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a and R7a are identical and are selected from:
C1-C4 alkyl or C3-C6 cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, xe2x80x94COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl, and
aryl or heteroaryl.
[21] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a is selected from:
H,
C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl,
aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl);
R7a is selected from:
C1-C4 alkyl and each such C1-C4 alkyl is substituted with 1-3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl.
[22] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein one of R6a and R7a is selected from:
C3-C6 cycloalkyl, each such C3-C6 cycloalkyl optionally substituted with 1-3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl,
aryl,
heteroaryl or
heterocyclyl,
and the other of R6a and R7a is unsubstituted C1-C4 alkyl.
[23] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a and R7a are independently H or C1-C10 alkyl, each such C1-C10 alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, R8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl.
[24] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R4 substituents, and R3 is NR6aR7a or OR7.
[25] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a is independently selected from:
H,
C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl,
aryl, aryl(C1-C4 alkyl)-, heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl);
R7a is independently selected at each occurrence from:
H,
C5-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15 aryl, heteroaryl or heterocyclyl,
aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl),
alternatively, NR6R7 and NR6aR7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups.
[26] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a and R7a are identical and are selected from:
C1-C4 alkyl or C3-C6 cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, xe2x80x94COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl, and
aryl or heteroaryl.
[27] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a and R7a are identical and are
C1-C4 alkyl, each such C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, xe2x80x94COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R5, aryl, heteroaryl or heterocyclyl.
[28] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a is selected from:
H,
C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13 COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15 aryl, heteroaryl or heterocyclyl,
aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl);
R7a is:
C1-C4 alkyl and each such C1-C4 alkyl is substituted with 1-3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl.
[29] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein one of R6a and R7a is selected from:
C3-C6 cycloalkyl, each such C3-C6 cycloalkyl optionally substituted with 1-3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl,
aryl,
heteroaryl or
heterocyclyl, and the other of R6a and R7a is unsubstituted Cl-C4 alkyl.
[30] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a and R7a are independently H or C1-C10 alkyl, each such C1-C10 alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, R8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl.
[31] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein
Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R4 substituents,
R3 is NR6aR7a or OR7 and
R1 and R2 are independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl.
[32] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a is independently selected from:
H,
C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl,
aryl, aryl(C1-C4 alkyl)-, heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl);
R7a is independently selected at each occurrence from:
H,
C5-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano OR15, SH, S(O)nR13, COR15, CO2R5, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8COR13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl,
aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl),
alternatively, NR6R7 and NR6aR7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups.
[33] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a and R7a are identical and are selected from:
C1-C4 alkyl or C3-C6 cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, xe2x80x94COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl, and
aryl or heteroaryl.
[34] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a and R7a are identical and are
C1-C4 alkyl, each such C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, xe2x80x94COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl.
[35] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a is selected from:
H,
C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, hetetoaryl or heterocyclyl,
aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl);
R7a is:
C1-C4 alkyl and each such C1-C4 alkyl is substituted with 1-3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl.
[36] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein one of R6a and R7a is selected from:
C3-C6 cycloalkyl, each such C3-C6 cycloalkyl optionally substituted with 1-3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl,
aryl,
heteroaryl or
heterocyclyl,
and the other of R6a and R7a is unsubstituted C1-C4 alkyl.
[37] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a and R7a are independently H or C1-C10 alkyl, each such C1-C10 alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, R8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl.
[38] Specifically preferred compounds of the above invention are compounds of Formula (50) 
and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof, selected from the group consisting of:
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(n-Pr)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(Et)(n-Bu), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94(n-Pr)(CH2cPr), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(CH2CH2OMe)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)(n-Bu), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)(CH2OMe), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(Et)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OEt)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(Me)(Ph), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(n-Pr)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)(n-Pr), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)(CH2OMe), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94OEt, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(Et)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(CH2CN)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Me)(CH2OMe), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94OCH(Et)(CH2OMe), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(n-Pr)(CH2cPr), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Me)(CH2N(Me)2), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(cPr)(CH2CH2CN), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(n-Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(n-Bu)(CH2CN), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)(CH2OMe), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is xe2x80x94N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)2, R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)(CH2OMe), R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(Et)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OEt)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2CH2OMe)(CH2OMe)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is morpholino, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(CH2CH2OMe)2, R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(Et)2, R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NH(c-Pr), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)2, R4a is CN, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(c-Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is xe2x80x94NCH(CH2OMe)2, R4a is Me, R4b is H, R4c is Br, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c is Br, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)2, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein a compound of Formula (50) wherein R3 is xe2x80x94N(Et)2, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)(CH2OMe), R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(CH2CH2OMe)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)(CH2CH2OMe), R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(c-Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(c-Pr)(CH2CH2CN), R4a is Cl, R4b is H R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is (S)xe2x80x94NHCH(CH2OMe)(CH2CH2OMe), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)(CH2CH2OMe), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Me, R4b is H, R4c is Br, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is Br, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NH(CH2OMe)(CH2-iPr), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is H, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is NMe2, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)(n-Pr), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OEt)(Et), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c is NMe2, R4 is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(Et)2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e H;
a compound of Formula (50) wherein R3 is xe2x80x94N(Et)2, R4a is Me, R4b is H, R4c is Br, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(Et)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Me, R4b is H, R4c is NMe2, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is (S)xe2x80x94NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is (S)xe2x80x94NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(c-Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NH(Et)(CH2CN), R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(Et)2, R4a is Me, R4b is Me, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(CH2CH2OMe)(CH2CH2OH), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(CH2CH2OMe)2, R4a is Me, R4b is Me, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Me, R4b is Me, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(CH2c-Pr)(n-Pr), R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(c-Pr) (CH2CH2CN), R4a is Me, R4b is Me, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(Et)2, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(CH2CH2OMe)2, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)(CH2OMe) R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(Et)2, R4a is Cl, R4b is H, R4c is CN, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(c-Pr)(CH2CH2CN), R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OH)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; and
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H.
[39] More specifically preferred is 4-(bis-(2-methoxyethyl)amino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine and isomers thereof, stereoisomeric form forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.
[40] More specifically preferred is 4-(bis-(2-methoxyethyl)amino)-2,7-dimethyl-8-(2,5-dimethyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.
[41] More preferred are compounds of the above invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein A is CR.
[42] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt, or pro-drug forms thereof.
[43] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R4 substituents.
[44] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R3 is NR6aR7a or OR7.
[45] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R4 substituents, and R3 is NR6aR7a or OR7.
[46] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Z is CR2.
[47] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R4 substituents.
[48] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R3 is NR6aR7a or OR7.
[49] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R4 substituents, and R3 is NR6aR7a or OR7.
[50] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a and R7a are independently H or C1-C10 alkyl, and each such C1-C10 alkyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, R8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl.
[51] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein
Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R4 substituents,
R3 is NR6aR7a or OR7 and
R1 and R2 are independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl.
[52] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a and R7a are independently H or C1-C10 alkyl, and each such C1-C10 alkyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, R8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl.
[53] Specifically preferred compounds of the above invention are compounds of Formula (51) 
and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof selected from the group consisting of:
a compound of Formula (51) wherein R3 is xe2x80x94NHCH(n-Pr)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94NHCH(CH2OMe)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94N(c-Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94N(CH2CH2OMe)2, R4a is Cl, R4b is H R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94NHCH(CH2OMe)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94N(Et)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94N(n-Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94N(n-Bu)(CH2CH2CN), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94NHCH(n-Pr)(CH2OMe), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94NHCH(CH2OMe)2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formuia (51) wherein R3 is (S)xe2x80x94NH(CH2CH2OMe)CH2OMe, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94NH(CH2CH2OMe)CH2OMe, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94NH(Et), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94NHCH(n-Pr)2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94NHCH(CH2OMe)2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is (S)xe2x80x94NH(CH2CH2OMe)CH2OMe, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94NH(CH2CH2OMe)CH2OMe, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94N(n-Pr)(CH2CH2CN) R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94N(Et)2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is (S)xe2x80x94NH(CH2CH2OMe)CH2OMe, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94NH(CH2CH2OMe)CH2OMe, R4a s Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94N(Et)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94N(c-Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94N(c-Pr)(CH2CH2CN), R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94NHCH(n-Pr)(CH2OMe), R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94NHCH(n-Pr)(CH2OMe), R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Br, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94N(CH2CH2OMe)2, R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94NHCH(CH2OMe)2, R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94N(Et)2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94N(Et)2, R4a is Cl, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Cl, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94N(CH2CH2OMe)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94NHCH(CH2OMe)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is
a compound of Formula (51) wherein R3 is xe2x80x94N(Pr)(CH2CH2CN), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94N(Bu)(Et), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94NHCH(Et)CH2OMe, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is xe2x80x94NEt2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H; and
a compound of Formula (51) wherein R3 is xe2x80x94N(Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H.
[54] More specifically preferred is 7-(3-pentylamino)-2,5-dimethyl-3-(2-methyl-4-methoxyphenyl)-[1,5-a]-pyrazolopyrimidine and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.
[55] More specifically preferred is 7-(Diethylamino)-2,5-dimethyl-3-(2-methyl-4-methoxyphenyl-[1,5-a]-pyrazolopyrimidine and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.
[56] More specifically preferred is 7-(N-(3-cyanopropyl)-N-propylamino)-2,5-dimethyl-3-(2,4-dimethylphenyl)-[1,5-a]-pyrazolopyrimidine and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.
The present invention also provides pharmaceutical compositions comprising compounds of Formulae (1) and (2) and a pharmaceutically acceptable carrier.
[1] The present invention still further comprises a method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer""s disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals comprising administering to the mammal a therapeutically effective amount of a compound of Formula (1): 
and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof, wherein:
Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar optionally substituted with 1 to 5 R4 groups and each Ar is attached to an unsaturated carbon atom;
R1 is independently selected at each occurrence from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halo, CN, C1-C4 haloalkyl, C1-C12 hydroxyalkyl, C2-C12 alkoxyalkyl, C2-C10 cyanoalkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, NR9R10, C1-C4 alkyl-NR9R10, NR9COR10, OR11, SH or S(O)nR12;
R2 is selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, C1-C4 hydroxyalkyl, halo, CN, xe2x80x94NR6R7, NR9COR10, xe2x80x94NR6S(O)nR7, S(O)nNR6R7, C1-C4 haloalkyl, xe2x80x94OR7, SH or xe2x80x94S(O)nR12;
R3 is selected from NR6aR7a and OR7;
R4 is independently selected at each occurrence from: C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, NO2, halo, CN, C1-C4 haloalkyl, NR6R7, NR8COR7, NR8CO2R7, COR7, OR7, CONR6R7, CO(NOR9)R7, CO2R7, or S(O)nR7, where each such C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl and C4-C12 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, NO2, halo, CN, NR6R7, NR8COR7, NR8CO2R7, COR7 OR7, CONR6R7, CO2R7, CO(NOR9)R7, or S(O)nR7;
R6, R7, R6a and R7a are independently selected at each occurrence from:
H,
C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl,
aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl);
xe2x80x83alternatively, NR6R7 and NR6aR7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups;
R8 is independently selected at each occurrence from H or C1-C4 alkyl;
R9 and R10 are independently selected at each occurrence from H, C1-C4 alkyl, or C3-C6 cycloalkyl;
R11 is selected from H, C1-C4 alkyl, C1-C4 haloalkyl, or C3-C6 cycloalkyl;
R12 is C1-C4 alkyl or C1-C4 haloalkyl;
R13 is selected from C1-C4 alkyl, C1-C4 haloalkyl, C2-C8 alkoxyaltyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl(C1-C4 alkyl)-, heteroaryl or heteroaryl(C1-C4 alkyl)-;
R15 and R16 are independently selected at each occurrence from H, C1-C6 alkyl, C3-C10 cycloalkyl, C4-C16 cycloalkylalkyl, except that for S(O)nR15, R15 cannot be H;
aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR15, COR15, CO2R15, OC(O)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15, NR16R15, and CONR16R15;
heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, indazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or 2,3-dihydrobenzofuranyl, each being optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR15, xe2x80x94COR15, CO2R15, OC(O)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15, NR16R15, and CONR16R15;
heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR15, COR15, CO2R15, OC(O)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15, NR15R16, and CONR16R15;
n is independently at each occurrence 0, 1 or 2.
[2] Further preferred methods of the present invention are methods of claim 1 wherein, in the compound of Formula (1), Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 R4 substituents.
[2] Further preferred methods of the present invention are methods of claim 1 wherein, in the compound of Formula (1), Ar is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-trimethylphenyl, R1 and R2 are CH3, and R3 is NR6aR7a.
[4] The present invention further comprises compounds of Formula (1): 
and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein:
Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar optionally substituted with 1 to 5 R4 groups and each Ar is attached to an unsaturated carbon atom;
R1 is independently selected at each occurrence from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halo, CN, C1-C4 haloalkyl, C1-C12 hydroxyalkyl, C2-C12 alkoxyalkyl, C2-C10 cyanoalkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, NR9R10, C1-C4 alkyl-NR9R10, NR9COR10, OR11, SH or S(O)nR12;
R2 is selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, C1-C4 hydroxyalkyl, halo, CN, xe2x80x94NR6R7, NR9COR10, xe2x80x94NR6S(O)nR7, S(O)nNR6R7, C1-C4 haloalkyl, xe2x80x94OR7, SH or xe2x80x94S(O)nR12;
R3 is selected from NR6aR7a and OR7;
R4 is independently selected at each occurrence from: C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, NO2, halo, CN, C1-C4 haloalkyl, NR6R7, NR8COR7, NR8CO2R7, COR7, OR7, CONR6R7, CO(NOR9)R7, CO2R7, or S(O)nR7, where each such C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl and C4-C12 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, NO2, halo, CN, NR6R7, NR8COR7, NR8CO2R7, COR7 OR7, CONR6R7, CO2R7, CO(NOR9)R7, or S(O)nR7;
R6, R7, R6a and R7a are independently selected at each occurrence from:
H,
C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl,
aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl),
xe2x80x83alternatively, NR6R7 and NR6aR7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups;
R8 is independently selected at each occurrence from H or C1-C4 alkyl;
R9 and R10 are independently selected at each occurrence from H, C1-C4 alkyl, or C3-C6 cycloalkyl;
R11 is selected from H, C1-C4 alkyl, C1-C4 haloalkyl, or C3-C6 cycloalkyl;
R12 is C1-C4 alkyl or C1-C4 haloalkyl;
R13 is selected from C1-C4 alkyl, C1-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl(C1-C4 alkyl)-, heteroaryl or heteroaryl(C1-C4 alkyl)-;
R15 and R16 are independently selected at each occurrence from H, C1-C6 alkyl, C3-C10 cycloalkyl, C4-C16 cycloalkylalkyl, except that for S(O)nR15, R15 cannot be H;
aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR15, COR15, CO2R15, OC(O)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15, NR16R15, and CONR16R15;
heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or 2,3-dihydrobenzofuranyl, each being optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR15, xe2x80x94COR15, CO2R15, OC(O)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15, NR16R15, and CONR16R15;
heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR15, COR15, CO2R15, OC(O)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15, NR15R16, and CONR16R15;
n is independently at each occurrence 0, 1 or 2;
with the provisos that:
(1) when R2 is H and R3 is xe2x80x94OR7 and R7 is H, then R1 is not H, OH or SH;
(2) when R1 is CH3 or C2H5 and R2 is H, and R3 is OH, NHC4H9, or N(C2H5)2, then Ar is not phenyl or m-CH3-phenyl;
(3) when R2 is H and Ar is pyridyl, pyrimidinyl or pyrazinyl, and R3 is NR6aR7a, then R6a and R7a are not H or alkyl;
(4) when R2 is SO2NR6R7, then R3 is not OH; and
(5) when R2 is xe2x80x94NR6SO2R7 or xe2x80x94SO2NR6R7, then R3 is not OH.
[5] Further preferred compounds of the present invention inclde compounds of claim 4 and isomers thereof, stereisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof with the additional provisos that: (1) when R1 is H, C1-C4 alkyl, halo, CN, C1-C12 hyroxyalkyl, C1-C4 alkoxyalkyl or SO2(C1-C4 alkyl) and R3 is NR6aR7a and R6a is unsubstituted C1-C4 alkyl, then R7a is not phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl, benzoduranyl, benzothiazolyl, indolyl or C3-C6 cycloalkyl; and (2) when R1 is H, C1-C4 alkyl, halo, CN, C1-C4 hydroxyalkyl, C1-C4 alkoxyalkyl or SO2(C1-C4 alkyl and R3 is NR6aR7a and R7a is unsubstituted C1 -C4 alkyl, then R6a is not phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl, benzofuranyl, benzothiazolyl, indolyl or C3-C6 cycloalkyl.
[6] Further preferred compounds of the present invention include compounds of claim 4 and isomers thereof, steretsomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein: Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 R4 substituents.
[7] Further preferred compounds of the present invention include compounds of claim 6 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein: Ar is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-trimethylphenyl, and R1 and R2 are CH3.
[8] The present invention further provides for a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 4.
[9] The present invention further provides for a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 6.
[10] The present invention further provides for a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 7.
[11] Further preferred compounds of the present invention include compounds of claim 6 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein:
R6a is independently selected from:
H,
C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl,
aryl, aryl(C1-C4 alkyl)-, heteroaryl, heteroaryl(C1-C4 alkyl)-, heterocyclyl or heterocyclyl(C1-C4 alkyl)-; and
R7a is independently selected at each occurrence from:
H,
C5-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl,
aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl);
xe2x80x83alternatively, NR6R7 and NR6aR7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups.
[12] Further preferred compounds of the present invention include compounds of claim 6 and isomers hereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein:
R6a and R7a are identical and are selected from:
C1-C4 alkyl or C3-C6 cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, -COR15, CO2R15, OC(O)R13, NR8 COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl, and
aryl or heteroaryl.
[13] Further preferred compounds of the present invention include compounds of claim 6 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein:
R6a is selected from:
H,
C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 or 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl,
aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl); is selected from:
R7a is selected from:
C1-C4 alkyl and each such C1-C4 alkyl is substituted with 1-3 substituents independently selected at each occurrence from C1-C4 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloakyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R13, OC(O)R13, NR8COR15, N(COR15)2, NR8COR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl.
[14] Further preferred compounds of the present invention includes compounds of claim 6 and isomers hereof, stereoismeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts from thereof wherein:
one of R6a and R7a is selected from:
C3-C6 cycloalkyl, each such C3-C6 cycloalkyl optionally substituted with 1-3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl,
aryl,
heteroaryl or
heterocyclyl,
xe2x80x83and the other of R6a and R7a is unsubstituted C1-C4 alkyl.
[15] Further preferred compounds of the present invention include compounds of claim 6 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein R6a and R7a are independently H or C1-C10 alkyl, each such C1-C10 alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, R8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl.
[16] Further preferred compounds of the present invention include compounds of claim 4 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein:
Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R4 substituents;
R1 and R2 are independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl.
[17] Further preferred compounds of the present invention include compounds of claim 11 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein:
Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R4 substituents;
R1 and R2 are independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl.
[18] Further preferred compounds of the present invention include compounds of claim 12 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein:
Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R4 substituents;
R1 and R2 are independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl.
[19] Further preferred compounds of the present invention include compounds of claim 13 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein:
Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R4 substituents;
R1 and R2 are independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl.
[20] Further preferred compounds of the present invention include compounds of claim 14 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein:
Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R4 substituents;
R1 and R2 are independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl.
[21] Further preferred compounds of the present invention include compounds of claim 16 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein:
one of R6a and R7a is selected from:
C3-C6 cycloalkyl, each such C3-C6 cycloalkyl optionally substituted with 1-3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl,
aryl,
heteroaryl or
heterocyclyl,
xe2x80x83and the other of R6a and R7a is unsubstituted C1-C4 alkyl.
[22] Further preferred compounds of the present invention include compounds of claim 16 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein
R6a and R7a are independently H or C1-C10 alkyl, each such C1-C10 alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, R8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl.
[23] Further preferred compounds of the present invention include compounds of claim 4 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein R1 is independently selected at each occurrence from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C12 hydroxyalkyl, C2-C12 alkoxyalkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl.
[24] Further preferred compounds of the present invention include compounds of claim 4 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein R2 is selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, C1-C4 hydroxyalkyl, halo, CN, xe2x80x94NR6R7, C1-C4 haloalkyl, xe2x80x94OR7.
[25] Further preferred compounds of the present invention include compounds of claim 4 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein R4 is independently selected at each occurrence from: H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, halo, CN, C1-C4 haloalkyl, NR6R7, COR7, OR7, S(O)n(C1-C10 alkyl), where each such C1-C10 alkyl, C2-C10 alkenyl, C2-C3-C6 cycloalkyl and C4-C12 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, NR6R7, COR7 OR7, CO2R7 and where R7 in SONR7 is C1-C10 alkyl.
[26] Further preferred compounds of the present invention include compounds of claim 4 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein R4 is independently selected at each occurrence from: H, C1-C10 alkyl, C1-C4 alkoxy, halo, CN and xe2x80x94NR6R7.
[27] Further preferred compounds of the present invention include compounds of Formula (50) 
and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof, selected from the group consisting of:
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(n-Pr)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(CH2CH2OMe)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)(n-Bu), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)(CH2OMe), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(Et)2, R4a is C, R4b is M, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OEt)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of formula (50) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(Me)(Ph), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)(n-Pr), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)(CH2OMe), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94OEt, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(Et)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(CH2CN)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Me)(CH2OMe), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94OCH(Et)(CH2OMe), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(n-Pr)(CH2cPr), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Me)(CH2N(Me)2), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(cPr)(CH2CH2CN), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(n-Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(n-Bu)(CH2CN), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)(CH2OMe), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is xe2x80x94N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)2, R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)(CH2OMe), R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(Et)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OEt)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2CH2OMe)(CH2OMe), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is morpholino, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(CH2CH2OMe)2, R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NH(c-Pr), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)2, R4a is CN, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(c-Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is xe2x80x94NCH(CH2OMe)2, R4a is Me, R4b is H, R4c is Br, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c is Br, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)2, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)(CH2OMe), R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(CH2CH2OMe)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)(CH2CH2OMe), R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(c-Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(c-Pr)(CH2CH2CN), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is (S)xe2x80x94NHCH(CH2OMe)(CH2CH2OMe), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)(CH2CH2OMe), R4a is Cl, R4b is H, R4c is Cl, R4d is R and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Me, R4b is H, R4c is Br, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NH(CH2OMe)(CH2-iPr), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is H, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is NMe2, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)(n-Pr), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OEt)(Et), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c is NMe2, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(Et)2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(Et)2, R4a is Me, R4b is H, R4c is Br, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(Et)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Me, R4b is H, R4c is NMe2, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is (S)xe2x80x94NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is (S)xe2x80x94NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(c-Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NH(Et)(CH2CN), R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(Et)2, R4a is Me, R4b is Me, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(CH2CH2OMe)(CH2CH2OH), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(CH2CH2OMe)2, R4a is Me, R4b is Me, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Me, R4b is Me, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(CH2c-Pr)(n-Pr), R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(c-Pr)(CH2CH2CN), R4a is Me, R4b is Me, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)(CH2OMe), R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(Et)2, R4a is Cl, R4b is H, R4c is CN, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94N(c-Pr)(CH2CH2CN), R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(CH2OH)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; and
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is 2-ethylpiperid-1-yl, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is cyclobutyl-amino, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)CH2CHxe2x95x90CH2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)CH2CHxe2x95x90CH2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)CH2cPr, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)CH2cPr, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Pr)CH2cPr, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)Pr, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)Et, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)Bu, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)propargyl, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)propargyl, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(CH3)CH(CH3)CH3, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2CHxe2x95x90CH2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Me, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Et, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Pr, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2cPr, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(CH3)CH2CH3, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(cPr)2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is 2-ethylpiperid-1-yl, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is cyclobutyl-amino, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)CH2CHxe2x95x90CH2, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)CH2CHxe2x95x90CH2, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)CH2cPr, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)CH2cPr, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(Pr)CH2cPr, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)Pr, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)Et, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)Bu, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)propargyl, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)propargyl, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(CH3)CH(CH3)CH3, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2CHxe2x95x90CH2, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Me, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Et, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Pr, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2cPr, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(CH3)CH2CH3, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)2, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(cPr)2, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is xe2x80x94NHCH(Et)2, R4a is OMe, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is 2-ethylpiperid-1-yl, R4a is OMe, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is cyclobutyl-amino, R4a is OMe, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)CH2CHxe2x95x90CH2, R4a is OMe, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)CH2CHxe2x95x90CH2, R4a is OMe, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)CH2cPr, R4a is OMe, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)CH2cPr, R4a is OMe, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Pr)CH2cPr, R4a is OMe, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)Pr, R4a is OMe, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)Et, R4a is OMe, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)Bu, R4a is OMe, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)propargyl, R4a is OMe, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)propargyl, R4a is OMe, R4b is H, R4c is OMe, and R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(CH3)CH(CH3)CH3, R4a is OMe, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2CHxe2x95x90CH2, R4a is OMe, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Me, R4a is OMe, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Et, R4a is OMe, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Pr, R4a is OMe, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2cPr, R4a is OMe, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(CH3)CH2CH3, R4a is OMe, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(cPr)2, R4a is OMe, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)2, R4a is OMe, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(Et)2, R4a is OMe, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)2, R4a is OMe, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is 2-ethylpiperid-1-yl, R4a is OMe, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is cyclobutyl-amino, R4a is OMe, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)CH2CHxe2x95x90CH2, R4a is OMe, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)CH2CHxe2x95x90CH2, R4a is OMe, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)CH2cPr, R4a is OMe, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)CH2cPr, R4a is OMe, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(Pr)CH2cPr, R4a is OMe, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)Pr, R4a is OMe, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)Et, R4a is OMe, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)Bu, R4a is OMe, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)propargyl, R4a is OMe, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)propargyl, R4a is OMe, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(CH3)CH(CH3)CH3, R4a is OMe, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2CHxe2x95x90CH2, R4a is OMe, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Me, R4a is OMe, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Et, R4a is OMe, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Pr, R4a is OMe, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2cPr, R4a is OMe, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(CH3)CH2CH3, R4a is OMe, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(cPr)2, R4a is OMe, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)2, R4a is OMe, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(Et)2, R4a is OMe, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)2, R4a is OMe, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is 2-ethylpiperid-1-yl, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is cyclobutyl-amino, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is N(Me)CH2CHxe2x95x90CH2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is N(Et)CH2CHxe2x95x90CH2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is N(Me)CH2cPr, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is N(Et)CH2cPr, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is N(Pr)CH2cPr, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is N(Me)Pr, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is N(Me)Et, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is N(Me)Bu, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is N(Me)propargyl, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is N(Et)propargyl, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is NHCH(CH3)CH(CH3)CH3, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2CHxe2x95x90CH2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Me, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Et, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Pr, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2cPr, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is NHCH(CH3)CH2CH3, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is NHCH(Et)2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is NHCH(cPr)2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is NHCH(Et)2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is 2-ethylpiperid-1-yl, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is cyclobutyl-amino, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(Me)CH2CHxe2x95x90CH2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(Et)CH2CHxe2x95x90CH2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(Me)CH2cPr, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(Et)CH2cPr, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(Pr)CH2cPr, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(Me)Pr, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(Me)Et, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(Me)Bu, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(Me)propargyl, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(Et)propargyl, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is NHCH(CH3)CH(CH3)CH3, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2CHxe2x95x90CH2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Me, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Et, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Pr, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2cPr, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is NHCH(CH3)CH2CH3, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is NHCH(cPr)2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is NHCH(Et)2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(Et)2, R4a is Me, R4b is H R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is NHCH(Et)2, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is 2-ethylpiperid-1-yl, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is cyclobutyl-amino, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(Me)CH2CHxe2x95x90CH2, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(Et)CH2CHxe2x95x90CH2, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(Me)CH2cPr, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(Et)CH2cPr, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(Pr)CH2cPr, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(Me)Pr, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(Me)Et, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(Me)Bu, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(Me)propargyl, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(Et)propargyl, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is NHCH(CH3)CH(CH3)CH3, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2CHxe2x95x90CH2, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Me, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Et, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Pr, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2cPr, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is NHCH(CH3)CH2CH3, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is NHCH(cPr)2, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)2, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is NHCH(Et)2, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is N(Et)2, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is OMe;
a compound of Formula (50) wherein R3 is NHCH(Et)2, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is 2-ethylpiperid-1-yl, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is cyclobutyl-amino, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)CH2CHxe2x95x90CH2, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)CH2CHxe2x95x90CH2, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)CH2cPr, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)CH2cPr, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Pr)CH2cPr, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)Pr, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)Et, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)Bu, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)propargyl, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)propargyl, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(CH3)CH(CH3)CH3, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2CHxe2x95x90CH2, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Me, R4a is Cl, R4b H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Et, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Pr, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2cPr, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(CH3)CH2CH3, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(cPr)2, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)2, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(Et)2, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)2, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(Et)2, R4a is Cl, R4b is H, R4c is OMe, R4d is F and R4e is H;
a compound of Formula (50) wherein R3 is 2-ethylpiperid-1-yl, R4a is Cl, R4b is H, R4c is OMe, R4d is F and R4e is H;
a compound of Formula (50) wherein R3 is cyclobutyl-amino, R4a is Cl, R4b is H, R4c is OMe, R4d is F and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)CH2CHxe2x95x90CH2, R4a is Cl, R4b is H, R4c is OMe, R4d is F and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)CH2CHxe2x95x90CH2, R4a is Cl, R4b is H, R4c is OMe, R4d is F and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)CH2cPr, R4a is Cl, R4b is H, R4c is OMe, R4d is F and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)CH2cPr, R4a is Cl, R4b is H, R4c is OMe, R4d is F and R4e is H;
a compound of Formula (50) wherein R3 is N(Pr)CH2cPr, R4a is Cl, R4b is H, R4c is OMe, R4d is F and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)Pr, R4a is Cl, R4b is H, R4c is OMe, R4d is F and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)Et, R4a is Cl, R4b is H, R4c is OMe, R4d is F and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)Bu, R4a is Cl, R4b is H, R4c is OMe, R4d is F and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)propargyl, R4a is Cl, R4b is H, R4c is OMe, R4d is F and R4e is H;
a compound of Formula (50) wherein R3 is NH(CH(CH3)CH(CH3)CH3, R4a is Cl, R4b is H, R4c is OMe, R4d is F and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2CHxe2x95x90CH2, R4a is Cl, R4b is H, R4c is OMe, R4d is F and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Me, R4a is Cl, R4b is H, R4c is OMe, R4d is F and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Et, R4a is Cl, R4b is H, R4c is OMe, R4d is F and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Pr, R4a is Cl, R4b is H, R4c is OMe, R4d is F and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2cPr, R4a is Cl, R4b is H, R4c is OMe, R4d is F and R4e is H;
a compound of Formula (50) wherein R3 is NH(CH(CH3)CH2CH3, R4a is Cl, R4b is F, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(cPr)2, R4a is Cl, R4b is H, R4c is OMe, R4d is F and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)2, R4a is Cl, R4b is H, R4c is OMe, R4d is F and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(Et)2, R4a is Cl, R4b is H, R4c is OMe, R4d is F and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)2, R4a is Cl, R4b is H, R4c is OMe, R4d is F and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(Et)2, R4a is Cl, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is 2-ethylpiperid-1-yl, R4a is Cl, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is cyclobutyl-amino, R4a is Cl, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)CH2CHxe2x95x90CH2, R4a is Cl, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)CH2CHxe2x95x90CH2, R4a is Cl, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)CH2cPr, R4a is Cl, R4b is H, R4c is OMe, R4d is F and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)CH2cPr, R4a is Cl, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(Pr)CH2cPr, R4a is Cl, R4b is H, R4c is OMe, R4d is OM e and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)Pr, R4a is Cl, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)Et, R4a is Cl, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)Bu, R4a is Cl, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)propargyl R4a is Cl, R4b is H, R4c is H, R4d is OMe, and R4e is H;
a compound of Formula (50) wherein R3 is NH(CH(CH3)CH(CH3)CH3, R4a is Cl, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2CHxe2x95x90CH2, R4a is Cl, R4b is H, R4c is OMe R4d is F and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Me, R4a is Cl, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Et, R4a is Cl, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Pr, R4a is Cl, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2cPr, R4a is Cl, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(CH3)CH2CH3, R4a is Cl, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(cPr)2, R4a is Cl, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)2, R4a is Cl, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(Et)2, R4a is Cl, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)2, R4a is Cl, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(Et)2, R4a is Br, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is 2-ethylpiperid-1-yl, R4a is Br, R4b is H, R4c is OMe, R4d OMe and R4e is H;
a compound of Formula (50) wherein R3 is cyclobutyl-amino, R4a is Br, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)CH2CHxe2x95x90CH2, R4a is Br, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)CH2CHxe2x95x90CH2, R4a is Br, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)CH2cPr, R4a is Br, R4b is H, R4c is OMe, R4d is F and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)CH2cPr, R4a is Br, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(Pr)CH2cPr, R4a is Br, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)Pr, R4a is Br, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)Et, R4a is Br, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)Bu, R4a is Br, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)propargyl, R4a is Br, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is NH(CH(CH3)CH(CH3)CH3, R4a is Br, R4b is H, R4c is is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2CHxe2x95x90CH2, R4a is Br, R4b is H, R4c is OMe, R4d is F and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Me, R4a is Br, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Et, R4a is Br, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Pr, R4a is Br, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2cPr, R4a is Br, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is NH(CH(CH3)CH2CH3, R4a is Br, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(cPr)2, R4a is Br, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)2, R4a is Br, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(Et)2, R4a is Br, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)2, R4a is Br, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(Et)2, R4a is Me, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is 2-ethylpiperid-1-yl, R4a is Me, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is cyclobutyl-amino, R4a is Me, R4b is H, R4c is OMe and R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)CH2CHxe2x95x90CH2, R4a is Me, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)CH2CHxe2x95x90CH2, R4a is Me, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)CH2cPr, R4a is Me, R4b is H, R4c is OMe, R4d is F and R4e is H;
a compound of Formula (50) wherein R3 is N(Et)CH2cPr, R4a is Me, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(Pr)CH2cPr, R4a is Me, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)Pr, R4a is Me, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)Et, R4a is Me, R4b is, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)Bu, R4a is Me, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(Me)propargyl, R4a is Me, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is NH(CH(CH3)CH(CH3)CH3, R4a is Br, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2CHxe2x95x90CH2, R4a is Me, R4b is H, R4c is OMe, R4d is F and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Me, R4a is Me, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Et, R4a is Me, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)Pr, R4a is Br, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2cPr, R4a is Me, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is NH(CH(CH3)CH2CH3, R4a is Me, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(cPr)2, R4a is Me, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(Et)2, R4a is Me, R4b is H, R4c is OMe, R4d is OMe and R4e is H; and
a compound of Formula (50) wherein R3 is N(Et)2, R4a is Me, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
[28] Further preferred compounds of the present invention include compounds of claim 4 of Formula (60) 
and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof, selected from the group consisting of:
a compound of Formula (60) wherein R3 is NHCH(Et)2, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is 2-ethylpiperid-1-yl, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is cyclobutyl-amino, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)CH2CHxe2x95x90CH2, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Et)CH2cPr, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Pr)CH2cPr, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)Pr, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)Et, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)Bu, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)propargyl, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Et)propargyl, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is NH(CH(CH3)CH(CH3)CH3, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2CHxe2x95x90CH2, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)Me, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)Et, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)Pr, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2cPr, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is NH(CH(CH3)CH2CH3, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is NHCH(cPr)2 Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)2, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is NHCH(Et)2 Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Et)2, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is 2-ethylpiperid-1-yl, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is cyclobutyl-amino, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)CH2CHxe2x95x90CH2, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Et)CH2cPr, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Pr)CH2cPr, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)Pr, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)Et, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)Bu, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)propargyl, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is NH(CH(CH3)CH(CH3)CH3, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2CHxe2x95x90CH2, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Fotmula (60) wherein R3 is N(CH2CH2OMe)Me, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)Et, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)Pr, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2cPr, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is NH(CH(CH3)CH2CH3, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is NHCH(cPr)2, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)2, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is NHCH(Et)2, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Et)2, Ar is 6-dimethylamino-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is 2-ethylpiperid-1-yl, Ar is 6-methoxy-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is cyclobutyl-amino, Ar is 6-methoxy-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)CH2CHxe2x95x90CH2, Ar is 6-methoxy-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Et)CH2cPr, Ar is 6-methoxy-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Pr)CH2cPr, Ar is 6-methoxy-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)Pr, Ar is 6-methoxy-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)Et, Ar is 6-methoxy-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)Bu, Ar is 6-methoxy-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)propargyl, Ar is 6-methoxy-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Et)propargyl, Ar is 6-methoxy-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is NHCH(CH3)CH(CH3)CH3, Ar is 6-methoxy-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2CHxe2x95x90CH2, Ar is 6-methoxy-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)Me, Ar is 6-methoxy-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)Et, Ar is 6-methoxy-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)Pr, Ar is 6-methoxy-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2cPr, Ar is 6-methoxy-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is NHCH(CH3)CH2CH3, Ar is 6-methoxy-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is NHCH(cPr)2 Ar is 6-methoxy-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)2, Ar is 6-methoxy-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is NHCH(Et)2 Ar is 6-methoxy-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Et)2, Ar is 6-methoxy-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is 2-ethylpiperid-1-yl, Ar is 4-methoxy-6-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is cyclobutyl-amino, Ar is 4-methoxy-6-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)CH2CHxe2x95x90CH2, Ar is 4-methoxy-6-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Et)CH2cPr, Ar is 4-methoxy-6-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Pr)CH2cPr, Ar is 4-methoxy-6-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)Pr, Ar is 4-methoxy-6-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)Et, Ar is 4-methoxy-6-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)Bu, Ar is 4-methoxy-6-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)propargyl, Ar is 4-methoxy-6-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is NHCH(CH3)CH(CH3)CH3, Ar is 4-methoxy-6-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2CHxe2x95x90CH2, Ar is 4-methoxy-6-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)Me, Ar is 4-methoxy-6-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)Et, Ar is 4-methoxy-6-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)Pr, Ar is 4-methoxy-6-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2cPr, Ar is 4-methoxy-6-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is NH(CH(CH3)CH2CH3, Ar is 4-methoxy-6-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is NHCH(cPr)2, Ar is 4-methoxy-6-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)2, Ar is 4-methoxy-6-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is NHCH(Et)2, Ar is 6-methoxy-4-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Et)2, Ar is 4-methoxy-6-methylpyrid-3-yl;
a compound of Formula (60) wherein R3 is 2-ethylpiperid-1-yl, Ar is 4,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is cyclobutyl-amino, Ar is 4,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)CH2CHxe2x95x90CH2, Ar is 4,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Et)CH2cPr, Ar is 4,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Pr)CH2cPr, Ar is 4,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)Pr, Ar is 4,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)Et Ar is 4,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)Bu, Ar is 4,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)propargyl, Ar is 4,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Et)propargyl, Ar is 4,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is NHCH(CH3)CH(CH3)CH3, Ar is 4,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2CHxe2x95x90CH2, Ar is 4,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)Me, Ar is 4,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)Et, Ar is 4,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)Pr, Ar is 4,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2cPr, Ar is 4,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is NHCH(CH3)CH2CH3, Ar is 4,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is NHCH(cPr)2, Ar is 4,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)2, Ar is 4,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is NHCH(Et)2 Ar is 4,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Et)2, Ar is 4,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is 2-ethylpiperid-1-yl, Ar is 2,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is cyclobutyl-amino, Ar is 2,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)CH2CHxe2x95x90CH2, Ar is 2,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Et)CH2cPr, Ar is Ar is 2,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Pr)CH2cPr, Ar is Ar is 2,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)Pr, Ar is 2,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)Et, Ar is 2,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)Bu, Ar is 2,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(Me)propargyl, Ar is 2,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is NH(CH(CH3)CH(CH3)CH3, Ar is 2,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2CHxe2x95x90CH2, Ar is 2,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)Me, Ar is 2,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)Et, Ar is 2,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)Pr, Ar is 2,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)xe2x80x94CH2cPr, Ar is 2,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is NH(CH(CH3)CH2CH3, Ar is 2,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is NHCH(cPr)2, Ar is 2,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is N(CH2CH2OMe)2, Ar is 2,6-dimethylpyrid-3-yl;
a compound of Formula (60) wherein R3 is NHCH(Et)2, Ar is 2,6-dimethyl-pyrid-3-yl; and
a compound of Formula (60) wherein R3 is N(Et)2, Ar is 2,6-dimethyl-pyrid-3-yl.
[29] Further preferred compounds of the present invention include compounds of claim 4 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof, wherein said compound is selected from the group consisting of:
4-((2-butyl)amino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine;
4-((2-butyl)amino)-2,7-dimethyl-8-(2,5-dimethyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine;
4-((3-pentyl)amino)-2,7-dimethyl-8-(2,5-dimethyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine;
4-((3-pentyl)amino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine;
4-(N-cyclopropylmethyl-N-propylamino)-2,7-dimethyl-8(2-methyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine;
4-(N-cyclopropylmethyl-N-propylamino)-2,7-dimethyl-8-(2,5-dimethyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine;
4-(N-allyl-N-(2-methoxyethyl)amino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine;
4-(N-allyl-N-(2-methoxyethyl)amino)-2,7-dimethyl-8-(2,5-dimethyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine;
4-(diallylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine;
4-(diallylamino)-2,7-dimethyl-8-(2,5-dimethyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine;
4-(N-ethyl-N-(2-methoxyethyl)amino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine; and
4-(N-ethyl-N-(2-methoxyethyl)amino)-2,7-dimethyl-8-(2,5-dimethyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine.
[30] The present invention further provides for pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claims 6, 11, 16, 27, 28 and 29.
[31] The present invention further provides for a method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer""s disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals comprising administering to the mammal a therapeutically effective amount of a compound of claim claims 4, 6, 11, 16, 27, 28 and 29.
Many compounds of this invention have one or more asymmetric centers or planes. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are included in the present invention. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. The compounds may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, (enantiomeric and diastereomeric) and racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
The term xe2x80x9calkylxe2x80x9d includes both branched and straight-chain alkyl having the specified number of carbon atoms. Commonly used abbreviations have the following meanings: Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl. As is conventional, in a chemical structure drawing, a straight single bond attached to an atom at one end but with no atom designation at the other end indicates the presence of a methyl group at the unattached end of the bond. The prefix xe2x80x9cnxe2x80x9d means a straight chain alkyl. The prefix xe2x80x9ccxe2x80x9d means a cycloalkyl. The prefix xe2x80x9c(S)xe2x80x9d means the S enantiomer and the prefix xe2x80x9c(R)xe2x80x9d means the R enantiomer. Alkenylxe2x80x9d includes hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like. xe2x80x9cAlkynylxe2x80x9d includes hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like. xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain alkyl having the specified number of carbon atoms, substituted with 1 or more halogen; xe2x80x9calkoxyxe2x80x9d represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; xe2x80x9ccycloalkylxe2x80x9d is intended to include saturated ring groups, including mono-,bi- or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so forth. xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d includes fluoro, chloro, bromo, and iodo.
The term xe2x80x9csubstitutedxe2x80x9d, as used herein, means that one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced.
Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By xe2x80x9cstable compoundxe2x80x9d or xe2x80x9cstable structurexe2x80x9d is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term xe2x80x9cappropriate amino acid protecting groupxe2x80x9d means any group known in the art of organic synthesis for the protection of amine or carboxylic acid groups. Such amine protecting groups include those listed in Greene and Wuts, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d John Wiley and Sons, New York (1991) and xe2x80x9cThe Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference. Any amine protecting group known in the art can be used. Examples of amine protecting groups include, but are not limited to, the following: 1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl and benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d includes acid or base salts of the compounds of Formulae (1) and (2). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
Pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
xe2x80x9cProdrugsxe2x80x9d are considered to be any covalently bonded carriers which release the active parent drug of formula (I) or (II) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of formula (I) and (II) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formulas (I) and (II); and the like.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d of a compound of this invention means an amount effective to antagonize abnormal level of CRF or treat the symptoms of affective disorder, anxiety or depression in a host.
Some compounds of Formula (1) may be prepared from intermediate compounds of Formula (7), using the procedures outlined in Scheme 1: 
Compounds of Formula (7) (where Y is O) may be treated with a halogenating agent or sulfonylating agent in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from xe2x88x9280xc2x0 C. to 250xc2x0 C. to give products of Formula (8) (where X is halogen, alkanesulfonyloxy, arylsulfonyloxy or haloalkane-sulfonyloxy). Halogenating agents include, but are not limited to, SOCl2, POCl3, PCl3, PCl5, POBr3, PBr3 or PBr5. Sulfonylating agents include, but are not limited to, alkanesulfonyl halides or anhydrides (such as methanesulfonyl chloride or methanesulfonic acid anhydride), arylsulfonyl halides or anhydrides (such as p-toluenesulfonyl chloride or anhydride) or haloalkylsulfonyl halides or anhydrides (preferably trifluoromethanesulfonic anhydride). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from xe2x88x9220xc2x0 C. to 100xc2x0 C.
Compounds of Formula (8) may be reacted with compounds of Formula R3H (where R3 is defined as above except R3 is not SH, COR7, CO2R7, aryl or heteroaryl) in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from xe2x88x9280 to 250xc2x0 C. to generate compounds of Formula (1). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 0xc2x0 C. to 140xc2x0 C.
Scheme 2 delineates the procedures for converting intermediate compounds of Formula (7) (where Y is S) to some compounds of Formula (1). 
Compounds of Formula (7) (where Y is S) may be treated with an alkylating agent R13X (where R13 is defined as above, except R13 is not aryl or heteroaryl) in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from xe2x88x9280xc2x0 C. to 250xc2x0 C. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 10 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal hydroxides, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (prefereably N,N-di-isopropyl-N-ethyl amine or triethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from xe2x88x9280xc2x0 C. to 100xc2x0 C.
Compounds of Formula (12) (Formula (1) where R3 is SR13) may then be reacted with compounds of Formula R3H to give compounds of Formula (1), using the same conditions and reagents as were used for the conversion of compounds of Formula (8) to compounds of Formula (1) as outlined for Scheme 1 above. Alternatively, compounds of Formula (12) (Formula (1) where R3 is SR13) may be oxidized to compounds of Formula (13) (Formula (1) where R3 is S(O)nR13, n is 1,2) by treatment with an oxidizing agent in the presence of an inert solvent at temperatures ranging from xe2x88x9280xc2x0 C. to 250xc2x0 C. Oxidizing agents include, but are not limited to, hydrogen peroxide, alkane or aryl peracids (preferably peracetic acid or m-chloro-perbenzoic acid), dioxirane, oxone, or sodium periodate. Inert solvents may include, but are not limited to, alkanones (3 to 10 carbons, preferably acetone), water, alkyl alcohols (1 to 6 carbons), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane) or combinations thereof. The choices of oxidant and solvent are known to those skilled in the art (cf. Uemura, S., Oxidation of Sulfur, Selenium and Tellurium, in Comprehensive Organic Synthesis, Trost, B. M. ed., (Elmsford, N.Y.: Pergamon Press, 1991), 7, 762-769). Preferred reaction temperatures range from xe2x88x9220xc2x0 C. to 100xc2x0 C. Compounds of Formula (13) (Formula (1) where R3 is S(O)nR13, n is 1,2) may then be reacted with compounds of Formula R3H to give compounds of Formula (1), using the same conditions and reagents as were used for the conversion of compounds of Formula (8) to compounds of Formula (1) as outlined for Scheme (1) above.
Compounds of Formula (1), where R3 may be xe2x80x94NR8COR7, xe2x80x94N(COR7)2, xe2x80x94NR8CONR6R7, xe2x80x94NR8CO2R13, xe2x80x94NR6R7, xe2x80x94NR8SO2R7, may be prepared from compounds of Formula (7), where Y is NH, by the procedures depicted in Scheme 3. 
Reaction of compounds of Formula (7), where Y is NH, with alkylating agents, sulfonylating agents or acylating agents or sequential reactions with combinations thereof, in the presence or absence of a base in an inert solvent at reaction temperatures ranging from xe2x88x9280xc2x0 C. to 250xc2x0 C. may afford compounds of Formula (1), where R3 may be xe2x80x94NR8COR7, xe2x80x94N(COR7)2, xe2x80x94NR8CONR6R7, xe2x80x94NR8CO2R13, xe2x80x94NR6R7, xe2x80x94NR8SO2R7. Alkylating agents may include, but are not limited to, C1-C10 alkyl -halides, -tosylates, -mesylates or -triflates; C1-C10 haloalkyl(1-10 halogens)-halides, -tosylates, -mesylates or -triflates; C2-C8 alkoxyalkyl-halides, -tosylates, -mesylates or -triflates; C3-C6 cycloalkyl-halides, -tosylates, -mesylates or -triflates; C4-C12 cycloalkylalkyl-halides, -tosylates, -mesylates or -triflates; aryl(C1-C4 alkyl)-halides, -tosylates, -mesylates or -triflates; heteroaryl(C1-C4 alkyl)-halides, -tosylates, -mesylates or -triflates; or heterocyclyl(C1-C4 alkyl)-halides, -tosylates, -mesylates or -triflates. Acylating agents may include, but are not limited to, C1-C10 alkanoyl halides or anhydrides, C1-C10 haloalkanoyl halides or anhydrides with 1-10 halogens, C2-C8 alkoxyalkanoyl halides or anhydrides, C3-C6 cycloalkanoyl halides or anhydrides, C4-C12 cycloalkylalkanoyl halides or anhydrides, aroyl halides or anhydrides, aryl(C1-C4) alkanoyl halides or anhydrides, heteroaroyl halides or anhydrides, heteroaryl(C1-C4)alkanoyl halides or anhydrides, heterocyclylcarboxylic acid halides or anhydrides or heterocyclyl(C1-C4) alkanoyl halides or anhydrides. Sulfonylating agents include, but are not limited to, C1-C10 alkylsulfonyl halides or anhydrides, C1-C10 haloalkylsulfonyl halides or anhydrides with 1-10 halogens, C2-C8 alkoxyalkylsulfonyl halides or anhydrides, C3-C6 cycloalkylsulfonyl halides or anhydrides, C4-C12 cycloalkylalkylsulfonyl halides or anhydrides, arylsulfonyl halides or anhydrides, aryl(C1-C4 alkyl)-, heteroarylsulfonyl halides or anhydrides, heteroaryl(C1-C4 alkyl)sulfonyl halides or anhydrides, heterocyclylsulfonyl halides or anhydrides or heterocyclyl(C1-C4 alkyl)sulfonyl halides or anhydrides. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (prefereably di-isopropylethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0xc2x0 C. to 100xc2x0 C.
Scheme 4 delineates procedures, which may be employed to prepare intermediate compounds of Formula (7), where Y is O, S and Z is CR2. 
Compounds of the formula ArCH2CN are reacted with compounds of the formula R2CORb, where R2 is defined above and Rb is halogen, cyano, lower alkoxy (1 to 6 carbons) or lower alkanoyloxy (1 to 6 carbons), in the presence of a base in an inert solvent at reaction temperatures ranging from xe2x88x9278xc2x0 C. to 200xc2x0 C. to afford compounds of Formula (3). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal hydroxides, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), water, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0xc2x0 C. to 100xc2x0 C.
Compounds of Formula (3) may be treated with hydrazine-hydrate in the presence of an inert solvent at temperatures ranging from 0xc2x0 C. to 200xc2x0 C., preferably 70xc2x0 C. to 150xc2x0 C., to produce compounds of Formula (4). Inert solvents may include, but are not limited to, water, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Compounds of Formula (4) may be reacted with compounds of Formula (5) (where Rc is alkyl (1-6 carbons)) in the presence or absence of an acid in the presence of an inert solvent at temperatures ranging from 0xc2x0 C. to 200xc2x0 C. to produce compounds of Formula (6). Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), haloalkanoic acids (2-10 carbons, 1-10 halogens, such as trifluoroacetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Inert solvents may include, but are not limited to, water, alkanenitriles (1 to 6 carbons, preferably acetonitrile), halocarbons of 1 to 6 carbons and 1 to 6 halogens (preferably dichloromethane or chloroform), alkyl alcohols of 1 to 10 carbons (preferably ethanol), dialkyl ethers (4 to 12 carbons, preferably diethyl ether or di-isopropylether) or cyclic ethers such as dioxan or tetrahydrofuran. Preferred temperatures range from ambient temprature to 100xc2x0 C.
Compounds of Formula (6) may be converted to intermediate compounds of Formula (7) by treatment with compounds Cxe2x95x90Y(Rd)2 (where Y is O or S and Rd is halogen (preferably chlorine), alkoxy (1 to 4 carbons) or alkylthio (1 to 4 carbons)) in the presence or absence of a base in an inert solvent at reaction temperatures from xe2x88x9250xc2x0 C. to 200xc2x0 C. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkali metal carbonates, alkali metal hydroxides, trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred temperatures are 0xc2x0 C. to 150xc2x0 C.
Intermediate compounds of Formula (7), where Z is N, may be synthesized according the methods outlined in Scheme 5. 
Compounds of ArCH2CN are reacted with compounds of Formula RqCH2N3 (where Rq is a phenyl group optionally substituted by H, alkyl (1 to 6 carbons) or alkoxy (1 to 6 carbons) in the presence or absence of a base in an inert solvent at temperatures ranging from 0xc2x0 C. to 200xc2x0 C. to generate compounds of Formnula (9). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide, sodium ethoxide or potassium t-butoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal hydroxides, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from ambient temperature to 100xc2x0 C.
Compounds of Formula (9) may be treated with a reducing agent in an inert solvent at xe2x88x92100xc2x0 C. to 100xc2x0 C. to afford products of Formula (10). Reducing agents include, but are not limited to, (a) hydrogen gas in combination with noble metal catalysts such as Pd-on-carbon, PtO2, Pt-on-carbon, Rh-on-alumina or Raney nickel, (b) alkali metals (preferably sodium) in combination with liquid ammonia or (c) ceric ammonium nitrate. Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), water, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). The preferred reaction temperatures are xe2x88x9250xc2x0 C. to 60xc2x0 C. Compounds of Formula (9) are then converted to compounds of Formula (7) (where Z is N) via intermediates of Formula (11) using the reagents and reaction conditions outlined in Scheme 4 for the conversion of compounds of Formula (4) to compounds of Formula (7) (where Z is CR2).
Compounds of Formula (1) may also be prepared from compounds of Formula (7) (where Y is O, S and Z is defined above) as outlined in Scheme 6: 
Compounds of Formula (7) may be reacted with compounds of Formula R3H in the presence of a dehydrating agent in an inert solvent at reaction temperatures ranging from 0xc2x0 C. to 250xc2x0 C. Dehydrating agents include, but are not limited to, P2O5, molecular sieves or inorganic or organic acids. Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably glyme or diglyme), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or halocarbons of 1 to 10 carbons and 1 to 10 halogens (preferably chloroform). Preferred reaction temperatures range from ambient temperature to 150xc2x0 C.
Some compounds of Formula (1) (where A is N) may also be prepared by the methods shown in Scheme 7: 
Intermediate compounds of Formula (14), where Z is defined above, may be reacted with compounds of Formula R3C(ORe)3, where Re may be alkyl (1 to 6 carbons) in the presence or absence of an acid in an inert solvent at temperatures ranging from 0xc2x0 C. to 250xc2x0 C. Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 50xc2x0 C. to 150xc2x0 C.
Intermediate compounds of Formula (7) may also be synthesized by the reactions displayed in Scheme 8. 
Compounds of Formula (15), (where Y is OH, SH, NR6R7; Z is defined above, X is Br, Cl, I, O3SCF3 or B(ORxe2x80x3xe2x80x3)2 and Rxe2x80x3xe2x80x3 is H or alkyl (1 to 6 carbons)) may be reacted with a compound of Formula ArM (where M is halogen, alkali metal, ZnCl, ZnBr, ZnI, MgBr, MgCl, MgI, CeCl2, CeBr2 or copper halides) in the presence or absence of an organometallic catalyst in the presence or absence of a base in an inert solvents at temperatures ranging from xe2x88x92100xc2x0 C. to 200xc2x0 C. Those skilled in the art will recognize that the reagents ArM may be generated in situ. Organometallic catalysts include, but are not limited to, palladium phosphine complexes (such as Pd(PPh3)4), palladium halides or alkanoates (such as PdCl2(PPh3)2 or Pd(OAc)2) or nickel complexes (such as NiCl2(PPh3)2). Bases may include, but are not limited to, alkali metal carbonates or trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine). Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or water. Preferred reaction temperatures range from xe2x88x9280xc2x0 C. to 100xc2x0 C.
The choices of M and X are known to those skilled in the art (cf. Imamoto, T., Organocerium Reagents in Comprehensive Organic Synthesis, Trost, B. M. ed., (Elmsford, N.Y.: Pergamon Press, 1991), 1, 231-250; Knochel, P., Organozinc, Organocadmium and Organomercury Reagents in Comprehensive Organic Synthesis, Trost, B. M. ed., (Elmsford, N.Y.: Pergamon Press, 1991), 1, 211-230; Knight, D. W., Coupling Reactions between sp2 Carbon Centers, in Comprehensive Organic Synthesis, Trost, B. M. ed., (Elmsford, N.Y.: Pergamon Press, 1991), 3, 481-520).
Compounds of Formula (1) may also be prepared using the methods shown in Scheme 9. 
Compounds of Formula (16), where A, Z, R1 and R3 are defined above and X is Br, Cl, I, O3SCF3 or B(ORxe2x80x3xe2x80x3)2 and Rxe2x80x3xe2x80x3 is H or alkyl (1 to 6 carbons)) may be reacted with a compound of Formula ArM (where M is halogen, alkali metal, ZnCl, ZnBr, ZnI, MgBr, MgCl, MgI, CeCl2, CeBr2 or copper halides) in the presence or absence of an organometallic catalyst in the presence or absence of a base in an inert solvents at temperatures ranging from xe2x88x92100xc2x0 C. to 200xc2x0 C. Those skilled in the art will recognize that the reagents ArM may be generated in situ (see the above references in Comprehensive Organic Synthesis). Organometallic catalysts include, but are not limited to, palladium phosphine complexes (such as Pd(PPh3)4), palladium halides or alkanoates (such as PdCl2(PPh3)2 or Pd(OAc)2) or nickel complexes (such as NiCl2(PPh3)2). Bases may include, but are not limited to, alkali metal carbonates or trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine). Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or water. Preferred reaction temperatures range from xe2x88x9280xc2x0 C. to 100xc2x0 C.
Intermediate compounds of Formula (7) (where Y is O, S, NH, Z is CR2 and R1, R2 and Ar are defined as above) may be prepared as illustrated in Scheme 10. 
Compounds of Formula (3) may be reacted with compounds of Formula H2NNH(Cxe2x95x90Y)NH2, where Y is O, S or NH, in the presence or absence of a base or acid in an inert solvent at temperatures from 0xc2x0 C. to 250xc2x0 C. to produce compounds of Formula (17). Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 6 carbons), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane).
Preferred reaction temperatures range from 0xc2x0 C. to 150xc2x0 C. Compounds of Formula (17) may then be reacted with compounds of Formula R3C(ORe)3, where Re may be alkyl (1 to 6 carbons) in the presence or absence of an acid in an inert solvent at temperatures ranging from 0xc2x0 C. to 250xc2x0 C. Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 50xc2x0 C. to 150xc2x0 C.
In Scheme 11, the procedures which may be used to convert compounds of Formula (1), where R3 is COR7, CO2R7, NR8COR7 and CONR6R7, to other compounds of Formula (1), where R3 is CH(OH)R7, CH2OH, NR8CH2R7 and CH2NR6R7 by treatment with a reducing agent in an inert solvent at temperatures ranging from xe2x88x9280xc2x0 C. to 250xc2x0 C. 
Reducing agents include, but are not limited to, alkali metal or alkaline earth metal borohydrides (preferably lithium or sodium borohydride), borane, dialkylboranes (such as di-isoamylborane), alkali metal aluminum hydrides (preferably lithium aluminum hydride), alkali metal (trialkoxy)aluminum hydrides, or dialkyl aluminum hydrides (such as di-isobutylaluminum hydride). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 6 carbons), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from xe2x88x9280xc2x0 C. to 100xc2x0 C.
In Scheme 12, the procedures are shown which may be used to convert compounds of Formula (1), where R3 is COR7 or CO2R7, to other compounds of Formula (1), where R3 is C(OH)(R7)2 by treatment with a reagent of Formula R7M in an inert solvent at temperatures ranging from xe2x88x9280xc2x0 C. to 250xc2x0 C. 
M is halogen, alkali metal, ZnCl, ZnBr, ZnI, MgBr, MgCl, MgI, CeCl2, CeBr2 or copper halides. Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from xe2x88x9280xc2x0 C. to 100xc2x0 C.
Compounds of Formula (1), where R3 may be xe2x80x94NR8COR7, xe2x80x94N(COR7)2, xe2x80x94NR8CONR6R7, xe2x80x94NR8CO2R13, xe2x80x94NR6R7, xe2x80x94NR8SO2R7, may be synthesized as depicted in Scheme 13. 
Reaction of compounds of Formula (18), where R and R1 are defined above, with compounds of Formula (4) or (10) in the presence or absence of base in an inert solvent may produce compounds of Formula (19) at temperatures ranging from xe2x88x9250xc2x0 C. to 250xc2x0 C. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (prefereably di-isopropylethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0xc2x0 C. to 100xc2x0 C.
Compounds of Formula (19) may then be reacted with alkylating agents, sulfonylating agents or acylating agents or sequential reactions with combinations thereof, in the presence or absence of a base in an inert solvent at reaction temperatures ranging from xe2x88x9280xc2x0 C. to 250xc2x0 C. may afford compounds of Formula (1), where R3 may be xe2x80x94NR8COR7, xe2x80x94N(COR7)2, xe2x80x94NR8CONR6R7, xe2x80x94NR8CO2R13, xe2x80x94NR6R7, xe2x80x94NR8SO2R7. Alkylating agents may include, but are not limited to, C1-C10 alkyl -halides, -tosylates, -mesylates or -triflates; C1-C10 haloalkyl(1-10 halogens)-halides, -tosylates, -mesylates or -triflates; C2-C8 alkoxyalkyl-halides, -tosylates, -mesylates or -triflates; C3-C6 cycloalkyl-halides, -tosylates, -mesylates or -triflates; C4-C12 cycloalkylalkyl-halides, -tosylates, -mesylates or -triflates; aryl(C1-C4 alkyl)-halides, -tosylates, -mesylates or -triflates; heteroaryl(C1-C4 alkyl)-halides, -tosylates, -mesylates or -triflates; or heterocyclyl(C1-C4 alkyl)-halides, -tosylates, -mesylates or -triflates. Acylating agents may include, but are not limited to, C1-C10 alkanoyl halides or anhydrides, C1-C10 haloalkanoyl halides or anhydrides with 1-10 halogens, C2-C8 alkoxyalkanoyl halides or anhydrides, C3-C6 cycloalkanoyl halides or anhydrides, C4-C12 cycloalkylalkanoyl halides or anhydrides, aroyl halides or anhydrides, aryl(C1-C4) alkanoyl halides or anhydrides, heteroaroyl halides or anhydrides, heteroaryl(C1-C4)alkanoyl halides or anhydrides, heterocyclylcarboxylic acid halides or anhydrides or heterocyclyl(C1-C4) alkanoyl halides or anhydrides. Sulfonylating agents include, but are not limited to, C1-C10 alkylsulfonyl halides or anhydrides, C1-C10 haloalkylsulfonyl halides or anhydrides with 1-10 halogens, C2-C8 alkoxyalkylsulfonyl halides or anhydrides, C3-C6 cycloalkylsulfonyl halides or anhydrides, C4-C12 cycloalkylalkylsulfonyl halides or anhydrides, arylsulfonyl halides or anhydrides, aryl(C1-C4 alkyl)-, heteroarylsulfonyl halides or anhydrides, heteroaryl(C1-C4 alkyl)sulfonyl halides or anhydrides, heterocyclylsulfonyl halides or anhydrides or heterocyclyl(C1-C4 alkyl)sulfonyl halides or anhydrides. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (prefereably di-isopropylethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0xc2x0 C. to 100xc2x0 C.
Compounds of Formula (1), where A is CR and R is defined above, may be synthesized by the methods depicted in Scheme 14. 
Compounds of Formula (4) or (10) may be treated with compounds of Formula (20), where R1 and R3 are defined above in the presence or absence of base in an inert solvent at temperatures ranging from 0xc2x0 C. to 250xc2x0 C. to give compounds of Formula (1), where A is CR and R is defined above. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably di-isopropylethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0xc2x0 C. to 100xc2x0 C. Alternatively, compounds of Formula (1) where A is CR and R is defined above, may be synthesized through intermediates (22) and (23).
Compounds of Formula (4) or (10) may be treated with compounds of Formula (21), where R1 is defined above and Re is alkyl (1-6 carbons), in the presence or absence of base in an inert solvent at temperatures ranging from 0xc2x0 C. to 250xc2x0 C. to give compounds of Formula (1), where A is CR and R is defined above. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (prefereably di-isopropylethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0xc2x0 C. to 100xc2x0 C. Compounds of Formula (22) may be treated with a halogenating agent or sulfonylating agent in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from xe2x88x9280xc2x0 C. to 250xc2x0 C. to give products of Formula (23) (where X is halogen, alkanesulfonyloxy, arylsulfonyloxy or haloalkanesulfonyloxy). Halogenating agents include, but are not limited to, SOCl2, POCl3, PCl3, PCl5, POBr3, PBr3 or PBr5. Sulfonylating agents include, but are not limited to, alkanesulfonyl halides or anhydrides (such as methanesulfonyl chloride or methanesulfonic acid anhydride), arylsulfonyl halides or anhydrides (such as p-toluenesulfonyl chloride or anhydride) or haloalkylsulfonyl halides or anhydrides (preferably trifluoromethanesulfonic anhydride). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from xe2x88x9220xc2x0 C. to 100xc2x0 C.
Compounds of Formula (23) may be reacted with compounds of Formula R3H (where R3 is defined as above except R3 is not SH, COR7, CO2R7, aryl or heteroaryl) in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from xe2x88x9280xc2x0 C. to 250xc2x0 C. to generate compounds of Formula (1). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 0xc2x0 C. to 140xc2x0 C.
Some compounds of Formula (1) may also be prepared using the methods shown in Scheme 15. 
A compound of Formula (24) (Rc is a lower alkyl group and Ar is defined as above) may be reacted with hydrazine in the presence or absence of an inert solvent to afford an intermediate of Formula (25), where Ar is defined as above. The conditions employed are similar to those used for the preparation of intermediate of Formula (4) from compound of Formula (3) in Scheme 4. Compounds of Formula (25), where A is N, may be reacted with reagents of the formula R1C(xe2x95x90NH)ORe, where R1 is defined above and Re is a lower alkyl group) in the presence or absence of an acid in an inert solvent, followed by reaction with a compound of formula YisC(Rd)2 (where Y is O or S and Rd is halogen (preferably chlorine), alkoxy (1 to 4 carbons) or alkylthio (1 to 4 carbons)) in the presence or absence of a base in an inert solvent to give compounds of Formula (27) (where A is N and Y is O, S). The conditions for these transformations are the same as those employed for the conversions of compound of Formula (4) to compound of Formula (7) in Scheme 4.
Alternatively, compounds of Formula (25), where A is CR, may be reacted with compounds of the formula R1(Cxe2x95x90O)CHR(Cxe2x95x90Y)ORc (where R1 and R are defined as above and Rc is a lower alkyl group) to give a compound of Formula (27) (where A is CR) using conditions similar to those employed for the conversion of compounds of Formula (21) to compounds of Formula (22) in Scheme 14. Intermediates of Formula (27) (where Y is O) may be treated with halogenating agents or sulfonylating agents in the presence or absence of a base in an inert solvent, followed by reaction with R3H or R2H in the presence or absence of a base in an inert solvent to give compounds of Formula (1) (where Z is CR2).
It will be recognized by those skilled in the art that various combinations of halogenating agents, sulfonylating agents, R3H or R2H may be used in different orders of reaction sequences in Scheme 15 to afford compounds of Formula (1). For example, in some cases, it may be desirable to react compounds with stoichiometric amounts of halogenating agents or sulfonylating agents, react with R2H (or R3H), then repeat the reaction with halogenating agents or sulfonylating agents and react with R3H (or R2H) to give compounds of Formula (1). The reaction conditions and reagents used for these conversions are similar to the ones employed for the conversion of intermediate compounds of Formulae (22) to (23) to (1) in Scheme 14 (for A is CR) or the conversion of intermediate compounds of Formulae (7) to (8) to (1) in Scheme 1 (where A is N).
Alternatively, compounds of Formula (27) (where Y is S) may be converted to compounds of Formula (1) in Scheme 15. Intermediate compounds of Formula (27) may be alkylated with a compound RfX (where Rf is lower alkyl and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in an inert solvent, (then optionally oxidized with an oxidizing agent in an inert solvent) and then reacted with R3H in the presence or absence of a base in an inert solvent to give a compound of Formula (1). The conditions and reagents employed are similar to those used in the conversion of intermediate compounds of Formulae (7) to (12) (or to (13)) to compounds of Formula (1) in Scheme 2.
Compounds of Formula (1) may be prepared from compounds of Formula (24), using an alternate route as depicted in Scheme 15. Compounds of Formula (24) may be converted to compounds of Formula (27) via reaction with compounds of formula NH2NH(Cxe2x95x90NH)NH2 in the presence or absence of an acid in an inert solvent, followed by reaction with compounds R1C(ORc)3 (where Rc is lower alkyl and R1 is defined as above), using the conditions employed for the conversion of compounds of Formulae (3) to (17) to (7) in Scheme 10.
Some compounds of Formula (2) may be prepared by the methods illustrated in Scheme 16. 
Compounds of Formula (27b) may be treated with various alkylating agents R14X (where R14 is defined above and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in the presence or absence of a base in an inert solvent to afford structures of Formula (28). Compounds of Formula (28) (Y is O) may then be converted to compounds of Formula (2) by treatment with halogenating agents or sulfonylating agents in the presence or absence of a base in an inert solvent, followed by reaction with R3H in the presence or absence of a base in an inert solvent to give compounds of Formula (2). The reaction conditions used for these conversions are similar to the ones employed for the conversion of intermediate compounds (22) to (23) to (1) in Scheme 14 (for A is CR) or the conversion of intermediate compounds of Formulae (7) to (8) to (1) in Scheme 1 (where A is N). Alternatively, compounds of Formula (28) (Y is S) may be alkylated with a compound RfX (where Rf is lower alkyl and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in an inert solvent, (then optionally oxidized with an oxidizing agent in an inert solvent) and then reacted with R3H in the presence or absence of a base in an inert solvent to give a compound of Formula (1). The conditions and reagents employed are similar to those used in the conversion of intermediate compounds of Formulae (7) to (12) (or to (13)) to compounds of Formula (1) in Scheme 2.
Compounds of Formula (1), where Z is COH, may be converted to compounds of Formula (2) as illustrated in Scheme 16. Treatment with various alkylating agents R14X (where R14 is defined above and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in the presence or absence of a base in an inert solvent to afford structures (2). It will be recognized by one skilled in the art that the methods used in Scheme 16 may also be used to prepare compounds of Formula (1) where Z is COR7.
For Scheme 16, the terms xe2x80x9cbasexe2x80x9d and xe2x80x9cinert solventxe2x80x9d may have the meanings given below. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from xe2x88x9220xc2x0 C. to 100xc2x0 C.